David Dunger

To test whether earlier age at weaning (age 3-6 months) may promote faster growth during infancy. Weaning at age 3.0-7.0 months was reported by 571 mothers of term singletons in a prospective birth cohort study conducted in Cambridge, UK. Infant weight and length were measured at birth and at age 3 months and 12 months. Anthropometric values were transformed into age- and sex-adjusted z-scores. Three linear regression models were performed, including adjustment for confounders in a stepwise manner. Measurements at age 3 months, before weaning, were used to consider reverse causality. Almost three-quarters (72.9%) of infants were weaned before age 6 months. Age at weaning of 3.0-7.0 months was inversely associated with weight and length (but not with body mass index) at 12 months (both P ≤ .01, adjusted for maternal and demographic factors). These associations were attenuated after adjustment for type of milk feeding and weight or length at age 3 months (before weaning). Rapid weight gain between 0 and 3 months predicted subsequent earlier age at weaning (P = .01). Our systematic review identified 2 trials, both reporting null effects of age at weaning on growth, and 15 observational studies, with 10 reporting an inverse association between age at weaning and infant growth and 4 reporting evidence of reverse causality. In high-income countries, weaning between 3 and 6 months appears to have a neutral effect on infant growth. Inverse associations are likely related to reverse causality.

Rapid early postnatal weight gain predicts increased subsequent obesity and related disease risks. However, the exact timing of adverse rapid postnatal weight gain is unclear. The objective was to examine the associations between rapid weight gain in infancy and in early childhood in relation to body composition at age 17 y. This prospective cohort study was conducted in 248 (103 males) singletons and their mothers. Height and weight were measured at birth, 6 mo, and 3 and 6 y. The rates of weight gain during infancy (0-6 mo) and early childhood (3-6 y) were calculated as changes in sex- and age-adjusted weight SD scores during these time periods. At 17 y, body composition was measured by air-displacement plethysmography. Increasing weight gain during infancy and early childhood were both independently associated with larger body mass index, fat mass, relative fat mass, fat-free mass, and waist circumference at 17 y (P < 0.005 for all; adjusted for sex, birth weight, gestational ...

We recently reported an association between common allelic variation (class I or class III) at the variable number of tandem repeat (VNTR) locus in the promoter region of the insulin gene (INS) and birthweight 1. In a contemporary, well-nourished group of 758 children, ...

The timing of puberty has considerable biological, psychosocial and long-term health implications. Secular trends in age at pubertal development, the effects of obesity and the potential effects of environmental endocrine disruptors challenge the standard definitions of precocious puberty and the indications for intervention with gonadotropin-releasing hormone agonists (GnRHa) in girls with precocious puberty. GnRHa therapy is effective in improving adult height in patients who present with classic central precocious puberty (at <8 years old), without causing adverse effects on body composition, BMD and reproductive function. However, its benefits in patients with atypical forms of early puberty not driven by luteinising hormone are not well defined. The role of GnRHa in these patients and the potential benefits in terms of later growth, psychosocial functioning and long-term risk of adult diseases that are associated with early menarche, such as breast cancer and the metabolic syndrome, have not been established.

Patterns of body size and body composition associated with genetic obesity susceptibility inform the mechanisms that increase obesity risk. To test associations between genetic obesity susceptibility, represented by a combined obesity risk-allele score, and body size or body composition at birth to age 5 years. A total of 3031 children from 4 birth cohort studies in England, France, and Spain were included in a meta-analysis. A combined obesity risk-allele score was calculated from genotypes at 16 variants identified by genome-wide association studies of adult body mass index (BMI). Outcomes were age- and sex-adjusted SD scores (SDS) for weight, length/height, BMI, fat mass, lean mass, and percentage of body fat at birth as well as at ages 1, 2 to 3, and 4 to 5 years. The obesity risk-allele score was not associated with infant size at birth; at age 1 year it was positively associated with weight (β [SE], 0.020 [0.008] SDS per allele; P = .009) and length (β [SE], 0.020 [0.008] SDS per allele; P = .01), but not with BMI (β [SE], 0.013 [0.008] SDS per allele; P = .11). At age 2 to 3 years these associations were stronger (weight: β [SE], 0.033 [0.008] SDS per allele; P < .001; height: β [SE], 0.025 [0.008] SDS per allele; P < .001) and were also seen for BMI (β [SE], 0.024 [0.008] SDS per allele; P = .003). The obesity risk-allele score was positively associated with both postnatal fat mass (1 year: β [SE], 0.032 [0.017] SDS per allele; P = .05; 2-3 years: β [SE], 0.049 [0.018] SDS per allele; P = .006; and 4-5 years: β [SE], 0.028 [0.011] SDS per allele; P = .009) and postnatal lean mass (1 year: β [SE], 0.038 [0.014] SDS per allele; P = .008; 2-3 years: β [SE], 0.064 [0.017] SDS per allele; P < .001; and 4-5 years: β [SE], 0.047 [0.011] SDS per allele; P < .001), but not with the percentage of body fat (P > .15 at all ages). Genetic obesity susceptibility appears to promote a normally partitioned increase in early postnatal, but not prenatal, growth. These findings suggest that symmetrical rapid growth may identify infants with high life-long susceptibility for obesity.

Size at birth, postnatal weight gain, and adult risk for type 2 diabetes may reflect environmental exposures during developmental plasticity and may be mediated by epigenetics. Both low birth weight (BW), as a marker of fetal growth restraint, and high birth weight (BW), especially after gestational diabetes mellitus (GDM), have been linked to increased risk of adult type 2 diabetes. We assessed DNA methylation patterns using a bead chip in cord blood samples from infants of mothers with GDM (group 1) and infants with prenatal growth restraint indicated by rapid postnatal catch-up growth (group 2), compared with infants with normal postnatal growth (group 3). Seventy-five CpG loci were differentially methylated in groups 1 and 2 compared with the controls (group 3), representing 72 genes, many relevant to growth and diabetes. In replication studies using similar methodology, many of these differentially methylated regions were associated with levels of maternal glucose exposure belo...

The aim of the study was to investigate the association between serum uric acid (SUA) and cardiovascular risk classes (CRCs) in adolescents using a cluster-based approach. A cross-sectional evaluation was carried out in the 2007-2008 school year, including adolescents born in 1990 and enrolled in the schools of Porto, Portugal. The analysis included 1,286 adolescents. To identify CRC, a normal mixture model was performed including several biological cardiovascular risk factors. A multinomial logistic regression model was applied to explore the association between SUA and each CRC. Three classes were extracted using model-based cluster analysis (low, medium, and high CRC). The high CRC accounted for the smallest proportion of participants (5.6%) and represented the adolescents with higher waist circumference, systolic and diastolic blood pressures, total cholesterol, triglycerides, and insulin levels. Adolescents at increased risk of cardiovascular disease had significantly higher me...

The masculinizing effects of prenatal androgens on human neurobehavioral development are well established. Also, the early postnatal surge of androgens in male infants, or mini-puberty, has been well documented and is known to influence physiological development, including penile growth. However, neurobehavioral effects of androgen exposure during mini-puberty are largely unknown. The main aim of the current study was to evaluate possible neurobehavioral consequences of mini-puberty by relating penile growth in the early postnatal period to subsequent behavior. Using multiple linear regression, we demonstrated that penile growth between birth and three months postnatal, concurrent with mini-puberty, significantly predicted increased masculine/decreased feminine behavior assessed using the Pre-school Activities Inventory (PSAI) in 81 healthy boys at 3 to 4years of age. When we controlled for other potential influences on masculine/feminine behavior and/or penile growth, including var...

To study the consequences of low birth weight on glucose and lipid metabolism 48 hours after delivery. We studied 136 small for gestational age (SGA) and 34 appropriate for gestational age (AGA) term neonates who were born in Santiago, Chile. Prefeeding venous blood was obtained 48 hours after birth for determination of glucose, free fatty acids, beta-hydroxy butyrate, insulin, C-peptide, leptin, sex hormone-binding globulin, insulin-like growth factor-binding protein-1 (IGFBP-1), and cortisol. SGA newborns had lower glucose (SGA versus AGA, median [interquartile range]: 3.6 mmol/L [2.9-4.1 mmol/L] vs 3.9 mmol/L [3.6-4.6 mmol/L]) and insulin levels (31.3 pmol/L [20.8-47.9 pmol/L] vs 62.5 pmol/L [53.5-154.9]) than AGA infants, and they had higher glucose/insulin ratios (13.9 mg/dL/uIU/mL [8.6-19.1 mg/dL/uIU/mL] vs 8.2 mg/dL/uIU/mL [4.6-14.1 mg/dL/uIU/mL]). SGA infants also had higher levels of IGFBP-1 (5.1 nmol/L [4.4-6.7 nmol/L] vs 2.9 nmol/l [1.4-4.2 nmol/L]), free fatty acids (0.72 mEq/L [0.43-1.00 mEq/L] vs 0.33 mEq/L [0.26-0.54 mEq/L]) and beta-hydroxy butyrate (0.41 mEq/L [0.15-0.91 mEq/L] vs 0.09 mEq/L [0.05-0.13 mEq/L]). Sex-hormone binding globulin levels were not significantly different between the 2 groups. In early postnatal life, SGA infants display an increased insulin sensitivity with respect to glucose disposal but not with respect to suppression of lipolysis, ketogenesis, and hepatic production of IGFBP-1. It will be important to determine how these differential sensitivities to insulin vary with increasing age.

Rapid infant weight gain has been shown to predict later obesity risk; however, it is unclear which factors influence infant diet and weight gain. The objective of this study was to determine whether different feeding patterns and energy intakes that are provided to infants affect body weight and BMI later in childhood. This representative birth cohort study was conducted in the United Kingdom. Energy intake at age 4 months was estimated from 1-day unweighed dietary records in 881 infants and related to their childhood weight gain and BMI. Among formula- or mixed-fed infants (N = 582), energy intake was higher in first-born infants (mean +/- SE: 2730 +/- 29.4 kJ/day; n = 263) than in subsequent-born infants (2620.8 +/- 25.2 kJ/day; n = 296). Energy intake at 4 months was also higher in infants who were given solid foods earlier (1-2 months: 2805.6 +/- 50.4 kJ/day, n = 89; 2-3 months: 2658.6 +/- 25.2 kJ/day, n = 339; 4+ months: 2587.2 +/- 46.2 kJ/day, n = 111). Higher energy intake at 4 months predicted greater weight gain between birth to age 1, 2, or 3 years and larger body weight and BMI at ages 1 to 5 years. No significant associations were seen in breastfed infants (N = 299). Among formula- or mixed-fed infants, dietary energy intake at age 4 months predicted postnatal weight gain and childhood obesity risk. Both prenatal and postnatal factors may influence infant energy intake and postnatal weight gain.

Among girls with precocious pubarche (PP), those with low birth weight (LBW) are, even if nonobese, at risk for progression to polycystic ovary syndrome (PCOS) including hyperinsulinemic hyperandrogenism, dyslipidemia, dysadipocytokinemia, and central fat excess. Recently, we disclosed the efficacy of insulin sensitization with metformin to disrupt progression from PP to PCOS in formerly LBW girls who were postmenarche. In LBW-PP girls, we have now extended the exploration of early insulin sensitization therapy in two directions: 1) metformin therapy was started before puberty; and 2) we assessed the effects of metformin discontinuation in girls who had started metformin treatment after menarche. Prepubertal LBW-PP girls (n = 33; mean age, 8.0 yr; body mass index, 18.5 kg/m(2)) were randomly assigned to remain untreated or to receive metformin (425 mg/d) for 6 months. Postpubertal LBW-PP girls (n = 24; age, 12.4 yr; body mass index, 21.0 kg/m(2)) had been randomized (at -12 months) to remain untreated or to receive metformin (850 mg/d) for 12 months, at which time (0 month) a treatment cross-over was performed for 6 months. Fasting blood glucose and serum insulin, SHBG, dehydroepiandrosterone sulfate, androstenedione, testosterone, lipid profile, IL-6, and adiponectin were assessed at 0 and 6 months, as was body composition (by dual x-ray absorptiometry). In the prepubertal study (group A), comparisons of untreated vs. treated girls disclosed normalizing effects of metformin on SHBG, androstenedione, dehydroepiandrosterone sulfate, low and high density lipoprotein cholesterol, triglycerides, IL-6, adiponectin, total and abdominal fat mass, and lean body mass. In the postpubertal study (group B), treatment cross-over at 0 month was in each subgroup followed by a striking reversal in the course of the endocrine-metabolic state, adipocytokinemia, and body composition; all changes pointed to normalizing effects of metformin treatment. In conclusion, these two studies provide the first evidence that 1) prepubertal metformin therapy has normalizing effects on PCOS features in high risk girls with a combined history of LBW and PP; and 2) in adolescence, metformin's normalizing effects are reversed as soon as metformin therapy is discontinued.

The endocrine-metabolic hallmarks of polycystic ovary syndrome are hyperinsulinism, hyperandrogenism, dyslipidemia, and anovulation. We hypothesized that dyslipidemia and anovulation in nonobese women with polycystic ovary syndrome are essentially secondary to the concerted effects of hyperandrogenism and insulin resistance. We tested this hypothesis by comparing the efficacy of anti-androgen (flutamide) or insulin-sensitizing (metformin) monotherapy to that of combined therapy in normalizing the endocrine-metabolic and anovulatory status of nonobese, young women with hyperinsulinemic hyperandrogenism. Thirty-one young women (mean age, 18.7 yr; body mass index, 21.9 kg/m(2); hirsutism score, 16; monthly ovulation rate monitored by weekly serum progesterone, 10%) were randomly assigned to receive once daily flutamide (250 mg; n = 10), metformin (1275 mg; n = 8), or combined flutamide- metformin therapy (n = 13) for 9 months. At baseline, there were no endocrine-metabolic differences among treatment groups. Compared with monotherapy, combined flutamide-metformin therapy resulted in greater improvements in insulin sensitivity, in testosterone, androstenedione, dehydroepiandrosterone sulfate, and triglyceride levels, and in low-density lipoprotein/high-density lipoprotein-cholesterol ratio (all P < 0.005). Monthly ovulation rates increased after 9 months to 75 and 92%, respectively, with metformin alone or with combined therapy, but were unimproved with flutamide alone. All treatments were well tolerated. In conclusion, combined anti-androgen and insulin-sensitizing treatment in young, nonobese women with hyperinsulinemic hyperandrogenism had additive benefits on insulin sensitivity, hyperandrogenemia, and dyslipidemia. The data from this small study suggest that dyslipidemia is secondary to excess androgen action in concert with the hyperinsulinemia associated with insulin resistance. In contrast, anovulation seems to be mainly attributable to insulin resistance and hyperinsulinemia.

Rapid infancy growth predicts childhood obesity and earlier rate of maturation. We examined whether early growth rates might also influence levels of hormones relating to growth and weight gain by measuring IGF-I, IGF-II, and leptin levels in 497 normal 5-yr-old children who were followed closely from birth. IGF-I levels at 5 yr were unrelated to cord blood IGF-I levels at birth (r = 0.03; P = 0.7; n = 166) but were positively related to current weight (r = 0.32; P < 0.0005) and height (r = 0.30; P < 0.0005) and inversely related to birthweight (r = -0.21; P < 0.0005). By body composition, IGF-I levels correlated more closely with fat-free mass (r = 0.22; P < 0.0005) than with fat mass (r = 0.12; P < 0.05), whereas leptin (r = 0.57; P < 0.0005) and IGF-II levels (r = 0.15; P < 0.005) correlated more closely with fat mass. Independent of current body composition, IGF-I levels at 5 yr were significantly associated with rate of weight gain between 0-2 yr (beta = 0.19; P < 0.0005), and children who showed postnatal catch-up growth (i.e. those who showed gains in weight or length between 0-2 yr by >0.67 SD score) had higher IGF-I levels than other children (P = 0.02). IGF-II levels at 5 yr were positively related to IGF-II levels at birth (r = 0.17; P = 0.03; n = 166), and leptin levels at 5 yr were mainly related to current adiposity. Circulating IGF-I levels in childhood are influenced by infancy growth rates and possibly mediate the effects of early postnatal nutrition on later rates of growth and maturation.

Overactivity of the hypothalamic-pituitary-adrenal axis through a program set by early growth patterns is hypothesized to lead to central obesity, insulin resistance, and hypertension. We therefore examined links between adrenal steroid production and birth weight, rapid early growth, and body mass index (BMI), blood pressure, waist circumference, and resistance to insulin in early childhood through the action of adrenal steroids. Timed overnight urine samples were collected in 461 children from a large representative birth cohort. In total 244 boys and 188 girls aged 8.2-8.4 yr completed the protocol. The excretion rates of individual steroids were measured to determine total androgen and cortisol metabolites. Indices of activity of 5alpha-androgen reduction of androgens and cortisol metabolites and 11beta-hydroxy steroid dehydrogenase activity were calculated. In both boys and girls, total urinary androgen and cortisol metabolites were positively related to current height, weight, BMI, and waist circumference. Girls had higher urine androgen metabolite levels and 5alpha-androgen indexes than boys, and in girls higher androgen metabolite excretion was associated with lower birth weight and faster postnatal weight gain. After adjustment for current BMI, total cortisol metabolites and 11beta-hydroxy steroid dehydrogenase index were not related to birth weight or postnatal weight gain in either sex. These data confirm early growth associations in this cohort seen with plasma levels of adrenal androgens at age 8 yr, at least in girls. Larger studies and follow-up during puberty are needed to exclude the possibility of programming of cortisol metabolism by early growth.

Recent discoveries of human genetic leptin deficiency have demonstrated its importance in regulating weight gain in early childhood. To investigate whether normal variation in leptin and insulin levels in cord blood could influence infancy growth, we assayed samples from 197 infants from a representative birth cohort, who were measured at birth, 4, 8, 12 and 24 months. Cord leptin levels correlated most closely with weight and ponderal index (kg/m3) at birth, but also with length and head circumference (all p<0.0005). Independent of birth size, females had higher leptin levels than males (p<0.0005). Cord levels of leptin, but not insulin, were negatively related to weight gain (p<0.005) from birth to 4 months, and accounted for 9.4% of the variance in weight gain, compared with breast/bottle feeding (3.5%) and early/late introduction of solids (1%). The effect of leptin levels on weight gain was independent of birthweight, and was still evident at 24 months. The wide variation in infancy growth ('catch-up' or 'catch-down') may be partly determined by leptin levels preset in utero. Our data support a role for leptin in the regulation of infancy weight gain, and suggest a mechanism whereby infants may 'catch-up' in growth postnatally following an adverse intrauterine environment.

Rapid postnatal weight gain has been associated with subsequent increased childhood adiposity. However, the contribution of rapid weight gain during specific infancy periods is not clear. We aimed to determine which periods of infancy weight gain are related to childhood adiposity and also to age at menarche in UK girls. A total of 2715 girls from a prospective UK birth cohort study participated in the study. Routinely measured weights and lengths at ages 2, 9, and 19 months were extracted from the local child health computer database. Body composition was assessed by dual-energy x-ray absorptiometry at age 10 yr, and age at menarche was assessed by questionnaire (categorized into three groups: <12.0, 12.0-13.0, and >13.0 yr). Faster early infancy weight gain between 0 and 2 months and also 2 to 9 months were associated with increased body fat mass relative to lean mass at age 10 yr and also with earlier age at menarche. Each +1 unit gain in weight sd score between 0 and 9 months was associated with an odds ratio (95% confidence interval) = 1.48 (1.27-1.60) for overweight (body mass index > 85th centile) at 10 yr, and 1.34 (1.21-1.49) for menarche at less than 12 yr. In contrast, subsequent weight gain between 9 and 19 months was not associated with later adiposity or age at menarche. In developed settings, rapid weight gain during the first 9 months of life is a risk factor for both increased childhood adiposity and early menarche in girls.

Adiponectin, a novel adipocytokine with insulin sensitizing properties, is inversely related to obesity and insulin resistance in adults. We recently reported large variations in weight gain and insulin sensitivity during the first year in infants born small for gestational age (SGA) or appropriate for gestational age (AGA). We now determined whether adiponectin levels were related to postnatal growth and insulin sensitivity in a prospective cohort followed from birth to two years old (n = 85) (55 female/30 male, 65 SGA/20 AGA). Serum adiponectin levels at one year and two years were higher compared to reported levels in adults and older children, and decreased from one year (21.6 +/- 0.6 microg/ml) to two years (15.7 +/- 0.7 microg/ml) (p < 0.05). At two years adiponectin levels were lower in females (15.3 +/- 0.4 microg/ml) than males (16.4 +/- 0.6 microg/ml) (p < 0.05), but no gender difference was seen in leptin or insulin levels. No differences in adiponectin levels were seen between SGA and AGA infants at one or two years. However, in SGA infants changes in adiponectin between one to two years old were inversely related to weight gain (r = -0.310, p < 0.05). Changes in leptin levels between one to two years were positively related to weight gain in both SGA and AGA infants (r = 0.450 and r = 0.500 respectively, both p < 0.05). Adiponectin levels were unrelated to insulin levels at one or two years, nor to change in insulin levels between one to two years. In multiple regression analysis, adiponectin levels were related only to postnatal age; omitting age from the model, the determinants of higher adiponectin levels were male gender (p = 0.03), lower postnatal body weight (p < 0.001), and higher birth weight SD score (p = 0.004). In conclusion, fall in serum adiponectin levels during the first two years of life were related to increasing age and greater weight gain SGA infants, but were unrelated to insulin sensitivity.

Ovarian hyperandrogenism is a common disorder often presenting post menarche with anovulatory oligomenorrhea and signs of androgen excess. Associated hyperinsulinemic insulin resistance, dyslipidemia, and central fat excess herald long-term disease risk. Combined antiandrogen (flutamide 250 mg/d) and insulin-sensitizing (metformin) therapy has beneficial effects, in particular on dyslipidemia and androgen excess in young women. We studied the effects of low-dose flutamide-metformin combination on metabolic variables and body composition in adolescent girls with ovarian hyperandrogenism. Thirty teenage girls (age range, 13.6-18.6 yr) with hyperinsulinemic hyperandrogenism participated in a 12-month pilot study with a 3-month off-treatment phase and a 9-month treatment phase (randomized sequence) on combined flutamide (125 mg/d) and metformin (1275 mg/d). Body composition was assessed by dual-energy x-ray absorptiometry; endocrine-metabolic state and ovulation rate were screened every 3 months. Insulin sensitivity was assessed by homeostasis model assessment (HOMA). Overnight GH and LH profiles were obtained pretreatment and after 6 months on treatment (n = 8). Over the 3-month pretreatment control phase (n = 14) all study indices were unchanged. Flutamide-metformin treatment (n = 30) was followed within 3 months by marked decreases in hirsutism score and serum androgens, by a more than 50% increase in insulin sensitivity and by a less atherogenic lipid profile (all P < 0.0001). After 9 months on flutamide-metformin, body fat decreased by 10%, with a preferential 20% loss of abdominal fat; conversely lean body mass increased, and total body weight remained unchanged; ovulation rate increased from 7-87% after 9 months. Baseline GH hypersecretion and elevated serum IGF-1 normalized after 6 months on flutamide-metformin. Within 3 months post treatment (n = 16), a rebound was observed for all assessed indices. In conclusion, in teenage girls with ovarian hyperandrogenism, low-dose combined flutamide-metformin therapy attenuated a spectrum of abnormalities, including insulin resistance and hyperlipidemia. Improved insulin sensitivity and reduced androgen activity led to a marked redistribution of body fat and lean mass, resulting in a more feminine body shape.

Wide ranges in postnatal weight gain are seen in infants born small for gestational age (SGA); most show some catch-up growth and this may be driven by increased appetite. Ghrelin, the natural ligand of the GH secretagogue receptor, has potent orexigenic effects. In adults circulating ghrelin levels are increased in anorexia, decreased in obesity and show post prandial suppression. The aim of the present study was to test the hypothesis that rate of weight gain over the first year in SGA infants may relate to variable suppression of circulating ghrelin levels. Serum ghrelin levels were measured in 1 y old infants born SGA (n = 85) and in control infants born adequate for gestatitional age (AGA) (n = 22) fasting and 10 minutes after intravenous (iv) glucose (0.5 g/Kg of 25% dextrose). Sex- and gestational age-adjusted SD scores (SDS) for body weight were calculated at birth and at 1 y, and delta weight SDS between 0-1 y was calculated as an index of postnatal weight gain. In both SGA and AGA groups, ghrelin levels reduced from fasting (mean +/- SE: 104.4 +/- 6.4 fmol/ml) to 10 minutes post-iv glucose (82.7 +/- 5.3, p < 0.005). There were no differences in ghrelin levels between SGA and AGA infants (fasting or post-iv glucose). However, in SGA infants ghrelin levels post-glucose, but not fasting, were psitively related to current length (r = 0.28, p < 0.05), weight (r = 0.23, p < 0.05) and to change in weight SDS 0-1 y (r = 0.22, p < 0.05). SGA infants who showed poor catch-up growth showed a larger decline in ghrelin concentrations post-iv glucose. In conclusion, circulating ghrelin levels rapidly decreased after iv glucose. Higher ghrelin levels or lower reductions in circulating levels following iv glucose were seen in SGA infants who showed greater infancy weight gain, suggesting that sustained orexigenic drive could contribute to postnatal catch-up growth.

A minority of children born small for gestational age (SGA) maintain a slow weight gain and a short stature (SS). At the other end of the spectrum are SGA children who show rapid postnatal weight gain and catch-up growth; these subjects may develop hyperinsulinemia, exaggerated adrenarche with precocious pubarche (PP), and an associated proinflammatory state with raised IL-6 and reduced adiponectin levels. Metformin therapy in SGA-PP girls attenuates the hyperinsulinemia, the adrenal androgen excess, and the proinflammatory state. In contrast, GH therapy in SGA-SS children promotes height gain but may induce hyperinsulinemia. Both groups are associated with increased risk markers for future cardiovascular disease. Therefore, we studied markers of inflammation in both SGA subpopulations at baseline and after their respectively corrective therapies. SGA-PP girls (n = 33; mean age, 8 yr; body mass index, 18.5 kg/m(2)) were randomized to remain untreated or to receive metformin (425 mg/d) for 6 months. SGA-SS children (n = 29; mean age, 7 yr; body mass index, 14.7 kg/m(2)) were randomly assigned to remain untreated or to receive GH (60 mug/kg/d). In SGA-PP girls, the mean neutrophil count (4.0 x 1000/mm(3)) was more than 2 sd above the mean reference level (2.8 x 1000/mm(3), P < 0.001); this remained stable over 6 months in untreated girls but dropped in metformin-treated girls by -1.1 x 1000/mm(3) (P = 0.002). In SGA-SS children, neutrophil counts were also higher at baseline (3.3 x 1000/mm(3), P < 0.01). This remained stable in untreated children but rose in GH-treated children by +1.1 x 1000/mm(3) (P = 0.004). GH-treated children also showed a rise in circulating IL-6 and dehydroepiandrosterone-sulfate levels and a fall in adiponectin levels. In conclusion, neutrophil counts were elevated in SGA children. In SGA girls with PP, the present results corroborate the antiinflammatory benefits of metformin therapy. In contrast, high-dose GH therapy in short SGA children may increase neutrophil counts and lead to a less favorable adipocytokine profile. Future studies with combined GH plus metformin treatment in short SGA children may clarify whether insulin resistance is a mechanism linking GH therapy to markers of inflammation.

Girls with precocious pubarche (PP, pubic hair at < 8 yr of age) are at high risk for early onset and rapid progression of puberty, in particular if their prenatal growth was restrained, i.e. low birth weight (LBW), and followed by rapid postnatal catch-up of weight gain. We postulated that insulin resistance contributes to early onset and rapid progression of puberty in LBW-PP girls and thus explored the puberty-delaying effects of insulin sensitization with metformin initiated shortly after PP diagnosis. The study population consisted of 38 prepubertal LBW girls with PP attributed to exaggerated adrenarche [mean body weight, 2.4 kg; age, 7.9 yr; body mass index (BMI), 18.4 kg/m(2)]. These girls were randomly assigned to remain untreated (n = 19) or to receive metformin (n = 19; 425 mg/d) for 2 yr. Pubertal staging, age at menarche, body composition by absorptiometry, fasting insulin, glucose, lipids, leptin, IGF-I, IGF-binding protein-1, testosterone, dehydroepiandrosterone sulfate, and SHBG were the main outcome measures. Metformin treatment was associated with a less adipose body composition (and lower serum leptin levels) and with a 0.4-yr delay in the clinical onset of puberty (Tanner B2; 9.5 vs. 9.1 yr; P < 0.01). These findings were corroborated by a delay of at least 1 yr in the puberty-associated rise of circulating IGF-I (P < 0.01). Available results also point to a metformin-associated delay of menarche (P < 0.02). Gain in height and lean mass was not divergent between study subgroups. The efficacy of early metformin treatment in PP girls is here extended to include not only a less adipose body composition after 2 yr but also a less advanced onset of puberty, whereas height gain is maintained. These findings open the perspective that, ultimately, metformin treatment may also prove to heighten the short adult stature of LBW-PP girls.